Project Summary The majority of people report eating highly palatable, calorically-dense ?comfort? foods as a means of stress relief. Indeed, individuals with a history of eating palatable foods have improved mood and reduced physiological and emotional responses to stress. However, comfort feeding comes at a significant cost to metabolic health, as stress-related eaters have higher BMIs and have more difficulty losing weight. Despite clear evidence that comfort feeding is a primary cause of obesity for many people, we know very little about why this is the case. This proposal addresses two critical gaps in our knowledge. First, it determines the mechanisms by which comfort feeding gives stress relief in normal weight individuals. Second, it identifies the extent that this stress relief is impaired during diet-induced obesity (DIO). This has important health implications, as it suggests a vicious cycle whereby obese individuals continually increase their consumption of palatable foods to maintain effective stress relief at the cost of worsening metabolic health. We propose to study these relationships using a palatable ?snacking? paradigm in which rats are given twice-daily access to a small amount of palatable sucrose solution, or water as a control. Rats given this limited sucrose intake (LSI) paradigm reduce their chow intake to compensate for the calories in the sucrose and maintain normal body weight, allowing us to isolate the mechanisms by which LSI reduces stress responses in normal weight individuals. Indeed, LSI rats have attenuated neuroendocrine (HPA axis), behavioral, and metabolic (energy mobilization) responses to a stress challenge. Moreover, LSI is unable to provide stress-blunting in DIO rats, suggesting that obesity may increase the amount of palatable food needed to obtain stress relief. The LSI paradigm therefore provides the unique opportunity to determine the mechanism underlying effective stress relief in normal weight rodents, how these mechanisms are disrupted by DIO, and whether DIO escalates sucrose intake thereby restoring effective stress relief at the cost of worsening metabolic health. Furthermore, our prior work implicates forebrain regions (BLA, mPFC) as key sites for LSI stress relief, though the neurocircuit mechanism that mediates this stress-blunting is not known. Our new preliminary data point to endocannabinoids (eCB; endogenous marijuana-like molecules) acting within this circuit as this mechanism. For instance, restraint stress rapidly increases BLA eCB (anandamide) content in LSI rats, but not water controls, and eCB signaling in the BLA is known to blunt stress responses. Systemic cannabinoid receptor type 1 antagonism also prevents LSI stress relief. This proposal therefore addresses the hypothesis that palatable foods curb stress responses by altering forebrain circuit function via eCB signaling during stress. The proposed experiments determine the contribution of PL-BLA projections and forebrain eCB-signaling to LSI stress relief. Experiments also test the extent to which DIO interferes with forebrain eCB signaling after LSI, as well as the ability of escalated sucrose consumption to recover forebrain eCB signaling and stress-blunting during DIO.